Project Summary Mantle cell lymphoma (MCL) has recently been recognized as a more complex NHL-B than the typical (small cell)/blastoid (large cell) dyad of the last two decades. Indolent, in situ, non-nodal MCL phenotypes indicate that MCL may represent a continuum from indolent lympho-proliferative disease (watch and wait) to the most aggressive disseminated blastoid MCL (hyper-CVAD). Validated patho-physiological and experimental therapeutic models of the MCL disease repertoire are serious unmet current needs for essential translational research in MCL. Based on our experimental studies, we are developing reproducible methodologies for generating both in vitro and in vivo MCL experimental models of MCL from patient samples. These models are based on developing extended growth and survival culture methods mediated by micro- environmental monocyte/macrophage MCL cell interactions. The signals that macrophages provide to induce MCL growth/survival and differentiation/transformation are completely unknown. In this proposal, we will utilize our novel in vitro MCL/macrophage co-culture systems and in vivo patient-derived xenotransplant MCL model systems to initially characterize and delineate the biologic functions of lymphoma- associated macrophages, and then elucidate potential pathways critical for the progression, dissemination and survival of MCL, as part of the MCL progression process from stable disease. This project is expected to provide novel insights into an unexplored area of MCL progression/transformation through microenvironment interactions that will not only fuel a better understanding of the disease process, but will facilitate the development of more mechanistic studies to identify novel druggable targets.